MODULE PHARMACOKINETICS WRITTEN SUMMARY

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1 MODULE PHARMACOKINETICS WRITTEN SUMMARY

2 m Pharmacokinetics Written Summary 2013N179518_00 TABLE OF CONTENTS PAGE 1. BRIEF SUMMARY METHODS OF ANALYSIS ABSORPTION DISTRIBUTION Dolutegravir: In Vitro Distribution Studies Inhibition of BSEP, OAT1, OAT3, MATE1, MATE2-K and MRP4-mediated transport METABOLISM EXCRETION PHARMACOKINETIC DRUG INTERACTIONS Dolutegravir: In Vitro Studies Mechanism based pharmacokinetic evaluation to predict the effect of dolutegravir on tenofovir kidney exposure OTHER PHARMACOKINETIC STUDIES DISCUSSION AND CONCLUSIONS TO PHARMACOKINETICS STUDIES REFERENCES

3 m Pharmacokinetics Written Summary 2013N179518_00 LIST OF TABLES PAGE Table 4.1 List of New Distribution Studies Performed with Dolutegravir...8 Table 7.1 List of New Pharmacokinetic Drug Interaction Studies Performed with Dolutegravir

4 m Pharmacokinetics Written Summary 2013N179518_00 1. BRIEF SUMMARY Since the submission of the original New Drug Application for dolutegravir (NDA ), 2 new pharmacokinetic studies have been completed. In one study, dolutegravir interactions with additional transporters were investigated in vitro, and in the other study, dolutegravir interactions with tenofovir was predicted using a physiological based pharmacokinetic model. No new previously unsubmitted pharmacokinetic studies have been conducted with abacavir or lamivudine. Dolutegravir: Summary of New Findings Absorption Distribution In vitro, dolutegravir did not inhibit human bile salt export pump (BSEP), but did inhibit multidrug resistance-associated protein 4 (MRP4), organic cation transporter 1 and 3 (OAT1 and OAT3) and multidrug and toxin extrusion transporter1 and 2-K (MATE1 and MATE2-K). Metabolism Excretion Drug interactions Following multiple once daily or twice daily dosing of 50 mg DTG, no significant change in the renal clearance or proximal tubule concentration of tenofovir was predicted in a physiological based pharmacokinetic (PBPK) mechanistic kidney model. Other PK studies 4

5 m Pharmacokinetics Written Summary 2013N179518_00 2. METHODS OF ANALYSIS 5

6 m Pharmacokinetics Written Summary 2013N179518_00 3. ABSORPTION 6

7 m Pharmacokinetics Written Summary 2013N179518_00 4. DISTRIBUTION The new distribution study with dolutegravir is listed in Table Dolutegravir: In Vitro Distribution Studies Inhibition of BSEP, OAT1, OAT3, MATE1, MATE2-K and MRP4-mediated transport An in vitro study was designed to evaluate the ability of dolutegravir to act as an inhibitor of the renal transporters, organic anion transporter 1 and 3 (OAT1, OAT3), multidrug and toxin extrusion transporters 1 and 2-K (MATE1, MATE2-K), and multidrug resistance protein 4 (MRP4), and the hepatic cannilicular transporter, bile salt export pump (BSEP) by measuring the transporter-mediated activity in the presence or absence of dolutegravir at concentrations of 0.1, 1, 3, 10, 30 and 100 M with an additional concentration of 120 M for MRP4 [Report 2013N161621]. A tabulated summary of this study is presented in m2.6.5, Table 8.1. Dolutegravir did not inhibit the BSEP-mediated uptake of [ 3 H]taurocholic acid (TCA) by membrane vesicles expressing human BSEP. The MRP4-mediated transport of [ 3 H]estradiol 17 -D-glucuronide (E2G) into membrane vesicles expressing human MRP4 was inhibited by dolutegravir with an IC 50 value of 84.4 ± 3.0 M. Dolutegravir inhibited the OAT1-mediated uptake of [ 3 H]para aminohippuric acid (PAH) and the OAT3-mediated transport of [ 3 H]estrone sulfate (ES) in S 2 cells expressing human OAT1 or OAT3 with respective IC 50 values of 2.12 M (OAT1) and 1.97 M (OAT3). Dolutegravir inhibited the MATE1-mediated and the MATE2-K-mediated uptake of [ 14 C]metformin in HEK293 cells transfected with a vector containing human MATE1 or MATE2-K cdna, with respective IC 50 values of 6.34 M (MATE1) and 24.8 M (MATE2-K). 7

8 m Pharmacokinetics Written Summary 2013N179518_00 Table 4.1 List of New Distribution Studies Performed with Dolutegravir Type of Study Species (Strain)/ Test System No./Sex/ Group Method of Administration Form Dose (mg/kg/day) or Concentration Duration of Dosing (Sampling Occasions) GLP Testing Facility Report No. (Study No.) Location in CTD Inhibition of BSEP, OAT1, OAT3, MATE1, MATE2-K and MRP4 transport Human NA In vitro A 0.1 to 100 or 120 M NA No 2013N (XS-0406) m Key: A = GSK A, the sodium salt form. BSEP = Bile salt export pump. MATE = Multidrug and toxin extrusion. MRP = Multidrug resistance associated protein. NA = Not applicable. OAT = Organic anion transporter. Testing Facility: = 8

9 m Pharmacokinetics Written Summary 2013N179518_00 5. METABOLISM 9

10 m Pharmacokinetics Written Summary 2013N179518_00 6. EXCRETION 10

11 m Pharmacokinetics Written Summary 2013N179518_00 7. PHARMACOKINETIC DRUG INTERACTIONS The new drug interaction study with dolutegravir is listed in Table Dolutegravir: In Vitro Studies Mechanism based pharmacokinetic evaluation to predict the effect of dolutegravir on tenofovir kidney exposure A mechanistic kidney pharmacokinetic model, as part of the SimCYP population based PBPK (physiologically based pharmacokinetic) simulator, was used to assess the effect of kidney OAT1, OAT3 and MRP4 inhibition by dolutegravir on the kidney exposure of tenofovir in humans at the clinically efficacious dose of dolutegravir [Report 2013N171682]. A tabulated summary of this study is presented in m2.6.5, Table Following multiple once daily or twice daily dosing of 50 mg dolutegravir, no significant change in the renal clearance or proximal tubule concentration of tenofovir was predicted. These simulations suggest that dolutegravir is not likely to influence the kidney disposition of tenofovir via inhibition of OAT1, OAT3 or MRP4. 11

12 m Pharmacokinetics Written Summary 2013N179518_00 Table 7.1 List of New Pharmacokinetic Drug Interaction Studies Performed with Dolutegravir Type of Study Species (Strain)/ Test System No./Sex/ Group Method of Administration Dose (mg/kg/day) Duration of Dosing (Sampling Occasions) GLP Testing Facility Report No. (Study No.) Location in CTD Drug interactions - Computer modelling Key: QD = Once per day. BID = Twice per day. NA = Not applicable. Human NA In silico 50 QD & BID orally Multiple No GSK 2013N m Testing Facility: GSK = GlaxoSmithKline. 12

13 m Pharmacokinetics Written Summary 2013N179518_00 8. OTHER PHARMACOKINETIC STUDIES 13

14 m Pharmacokinetics Written Summary 2013N179518_00 9. DISCUSSION AND CONCLUSIONS TO PHARMACOKINETICS STUDIES No new previously unsubmitted pharmacokinetic studies have been conducted with abacavir or lamivudine. In vitro, dolutegravir did not inhibit human bile salt export pump (BSEP), but did inhibit multidrug resistance associated protein 4 (MRP4), organic cation transporter 1 and 3 (OAT1 and OAT3) and multidrug and toxin extrusion transporter1 and 2-K (MATE1 and MATE2-K). Following multiple once daily or twice daily dosing of 50 mg dolutegravir, no significant change in the renal clearance or proximal tubule concentration of tenofovir was predicted in a physiological based pharmacokinetic (PBPK) mechanistic kidney model. The information generated by these additional studies with dolutegravir and reported after the initial submission does not alter the original interpretation of the safe clinical use of dolutegravir in the treatment of patients with HIV and supports the use of dolutegravir in combination with abacavir and lamivudine in HIV patients when prescribed under the recommended therapeutic dosage regimen. 14

15 m Pharmacokinetics Written Summary 2013N179518_ REFERENCES Not applicable. 15

16 MODULE PHARMACOKINETICS TABULATED SUMMARY

17 m Pharmacokinetics Tabulated Summary TABLE OF CONTENTS PAGE 1. PHARMACOKINETICS: OVERVIEW OF PREVIOUSLY UNSUBMITTED STUDIES CONDUCTED WITH DOLUTEGRAVIR COMPLETED SINCE THE INITIAL NDA ANALYTICAL METHODS AND VALIDATION REPORTS PHARMACOKINETICS: ABSORPTION AFTER A SINGLE DOSE PHARMACOKINETICS: ABSORPTION AFTER REPEATED DOSE PHARMACOKINETICS: ORGAN DISTRIBUTION PHARMACOKINETICS: PLASMA PROTEIN BINDING PHARMACOKINETICS: STUDY IN PREGNANT OR NURSING ANIMALS PHARMACOKINETICS: OTHER DISTRIBUTION STUDIES PHARMACOKINETICS: METABOLISM IN VIVO PHARMACOKINETICS: METABOLISM IN VITRO PHARMACOKINETICS: POSSIBLE METABOLIC PATHWAYS PHARMACOKINETICS: INDUCTION/INHIBITION OF DRUG METABOLISING ENZYMES PHARMACOKINETICS: EXCRETION PHARMACOKINETICS: EXCRETION INTO BILE PHARMACOKINETICS: DRUG-DRUG INTERACTIONS PHARMACOKINETICS: OTHER

18 m Pharmacokinetics Tabulated Summary LIST OF TABLES PAGE Table 1.1 List of New Distribution Studies Performed with Dolutegravir...4 Table 1.2 Listing of New Pharmacokinetic Drug-Drug Interaction Studies Performed with Dolutegravir...5 Table 8.1 Dolutegravir: In Vitro Inhibition of Human Transporters...12 Table 15.1 Pharmacokinetics: Dolutegravir - Other Distribution Studies

19 m Pharmacokinetics Tabulated Summary 1. PHARMACOKINETICS: OVERVIEW OF PREVIOUSLY UNSUBMITTED STUDIES CONDUCTED WITH DOLUTEGRAVIR COMPLETED SINCE THE INITIAL NDA Table 1.1 List of New Distribution Studies Performed with Dolutegravir Type of Study Species (Strain)/ Test System No./Sex/ Group Method of Administration Form Dose (mg/kg/day) or Concentration Duration of Dosing (Sampling Occasions) GLP Testing Facility Report No. (Study No.) Location in CTD Inhibition of BSEP, OAT1, OAT3, MATE1, MATE2-K and MRP4 transport Human NA In vitro A 0.1 to 100 or 120 M NA No 2013N (XS-0406) m Key: A = GSK A, the sodium salt form. BSEP = Bile salt export pump. MATE = Multidrug and toxin extrusion. MRP = Multidrug resistance associated protein. NA = Not applicable. OAT = Organic anion transporter. Testing Facility: = 4

20 m Pharmacokinetics Tabulated Summary Table 1.2 Listing of New Pharmacokinetic Drug-Drug Interaction Studies Performed with Dolutegravir Type of Study Species (Strain)/ Test System No./Sex/ Group Method of Administration Dose (mg/kg/day) Duration of Dosing (Sampling Occasions) GLP Testing Facility Report No. (Study No.) Location in CTD Drug interactions - Computer modelling Key: QD = Once per day. BID = Twice per day. NA = Not applicable. Human NA In silico 50 QD & BID orally Multiple No GSK 2013N m Testing Facility: GSK = GlaxoSmithKline. 5

21 m Pharmacokinetics Tabulated Summary 2. ANALYTICAL METHODS AND VALIDATION REPORTS 6

22 m Pharmacokinetics Tabulated Summary 3. PHARMACOKINETICS: ABSORPTION AFTER A SINGLE DOSE 7

23 m Pharmacokinetics Tabulated Summary 4. PHARMACOKINETICS: ABSORPTION AFTER REPEATED DOSE 8

24 m Pharmacokinetics Tabulated Summary 5. PHARMACOKINETICS: ORGAN DISTRIBUTION 9

25 m Pharmacokinetics Tabulated Summary 6. PHARMACOKINETICS: PLASMA PROTEIN BINDING 10

26 m Pharmacokinetics Tabulated Summary 7. PHARMACOKINETICS: STUDY IN PREGNANT OR NURSING ANIMALS 11

27 m Pharmacokinetics Tabulated Summary 8. PHARMACOKINETICS: OTHER DISTRIBUTION STUDIES Table 8.1 Dolutegravir: In Vitro Inhibition of Human Transporters Test Article: Dolutegravir Target Inhibition IC50 ( M) Report No. Location in CTD BSEP None 2013N m MATE N m MATE2-K N m MRP N m OAT N m OAT N m Additional Information: BSEP = Bile salt export pump transporter; tested with membrane vesicles expressing BSEP. MATE = Multidrug and toxin extrusion transporter; tested with HEK293 cells expressing MATE1 or MATE2-K. MRP = Multidrug resistance associated protein. None = No inhibition detected. OATP = Organic anion transporting polypeptide. 12

28 m Pharmacokinetics Tabulated Summary 9. PHARMACOKINETICS: METABOLISM IN VIVO 13

29 m Pharmacokinetics Tabulated Summary 10. PHARMACOKINETICS: METABOLISM IN VITRO 14

30 m Pharmacokinetics Tabulated Summary 11. PHARMACOKINETICS: POSSIBLE METABOLIC PATHWAYS 15

31 m Pharmacokinetics Tabulated Summary 12. PHARMACOKINETICS: INDUCTION/INHIBITION OF DRUG METABOLISING ENZYMES 16

32 m Pharmacokinetics Tabulated Summary 13. PHARMACOKINETICS: EXCRETION 17

33 m Pharmacokinetics Tabulated Summary 14. PHARMACOKINETICS: EXCRETION INTO BILE 18

34 m Pharmacokinetics Tabulated Summary 15. PHARMACOKINETICS: DRUG-DRUG INTERACTIONS Table 15.1 Pharmacokinetics: Dolutegravir - Other Distribution Studies Test Article: Dolutegravir Type of Study: A mechanism based pharmacokinetic evaluation to predict the effect of GSK on tenofovir kidney exposure. Study System: Method: Report No.: 2013N Location in CTD: m Physiological based pharmacokinetic (PBPK) mechanistic kidney model (Simcyp v,12 R1) developed for steady state concentrations of tenofovir (300 mg once daily) predict that co-administration of DTG at 50 mg once daily would result in a minimal decrease in tenofovir renal clearance with no notable change in tenofovir exposure within the proximal tubule cells of the kidney. The mechanism behind the potential interaction between GSK and tenofovir does not impact the pharmacokinetics of GSK , as demonstrated in Study ING [Report RM2008/00793/00], the clinically observed GSK primary pharmacokinetic parameters (i.e., CL/F and Vd/F) were entered into SimCYP for the purposes of the simulation, with only small modifications as needed to simulate a GSK plasma concentration curve similar to that observed in Report RM2008/00793/00. Tenofovir pharmacokinetics and kidney disposition were simulated using a mechanistic kidney model implemented in the Simcyp ADME simulator (Version 12, Release 2, Simcyp Ltd, Sheffield, UK). Simulation and Sensitivity Analysis Results Following Co-Administration of 300 mg Tenofovir QD for 12 Days with 50 mg GSK QD or BID on Days 8 to mg Tenofovir QD x 12 Days with 50 mg GSK QD Days 8 to 12 Median of Proximal Tubule C max Values (ng/ml) 1 Predicted Fold Change Median Renal Clearance (L/hr) Tenofovir alone Tenofovir in the presence of GSK Fold change

35 m Pharmacokinetics Tabulated Summary Pharmacokinetics: Dolutegravir - Other Distribution Studies (Continued) 300 mg Tenofovir QD x 12 Days with 50 mg GSK QD Days 8 to 12 (10-Fold Reduced Tenofovir Diffusion Clearance in Proximal Tubule) Median of Proximal Tubule C max Values (ng/ml) 1 Predicted Fold Change Median Renal Clearance (L/hr) Tenofovir alone Tenofovir in the presence of GSK Fold change mg Tenofovir QD x 12 Days with 50 mg GSK QD Days 8 to 12 (10-Fold Increased GSK Kidney:Blood Ratio) Tenofovir alone Tenofovir in the presence of GSK Fold change mg Tenofovir QD x 12 Days with 50 mg GSK BID Days 8 to 12 Tenofovir alone Tenofovir in the presence of GSK Fold change

36 m Pharmacokinetics Tabulated Summary 16. PHARMACOKINETICS: OTHER 21